`
`ENDO - Ex. 2038
`
`Amneal v. Endo
`
`|PR2014-00360
`
`ENDO - Ex. 2038
`Amneal v. Endo
`IPR2014-00360
`
`

`

`EDITION
`
`
`
`ir
`
`
`Senior Vice President, Directory Services: Paul Walsh
`
`Director of Product Management: Mark A. Friedman
`.
`Director, New~,Business~Development and
`.
`,4“.
`Associate Product Manager: Bil|.Shaughnessy
`Professional Support Services: Mukesh Mehta, RPh-
`Senior Business Manager: Mark S. Ritchin
`Manager, Drug Infomiation Services: Thomas Fleming, RPh
`Financial Analyst: Wayne M. Soltis
`Drug lnforrnationSpecgallst:Maria Deutsch, MS, RPh, ,CDE
`Director of‘S'éles: Dikran _N. Barsamian
`’
`'
`‘
`'
`Editor, Directory services: David W. Siftoh
`National Sales Manager, Pharmaceutical Sales: Anthony Sorce
`Senior Associate Editor: Lori Murray
`National Account Manager: Don Bruccoleri
`Director of Production: Carrie Williams
`Senior Account Manager: Frank Ka'rkowsky.
`Manager of Production:‘Kimberly H. Vivas
`Account Managers:
`Senior Production Coordinator: Amy B. Brooks
`Marion Gray. RPh
`Production Coordinators: Gianna Garado‘nna, Maria Volpati
`Lawrence C. Keary
`Data Manager: Jeffrey D. Schaefer
`Jeffrey F.. Pfohl
`Senior Format Editor: GregoryJ. Westley
`Suzanne 5- Yarrow, RN
`Index Editors: Johanna M. Mazur, Robert N. Woerner
`Electronic Sales Account Manager: Stephen M. Silverberg
`An Associate: Joan K. Akeriind
`National Sales Manager, Medical Economics Trade Sales: Bill Gaffney
`Senior Digital Imaging coordinator: ShaWn w. Cahill
`Director of Direct Marketing: Michael Bennett
`Digital Imaging Coordinator: Frank J. McElroy, lll
`List and Production Manager: Lorraine M. Loening
`Electronic Publishing DesignerLLivio Udina.
`Senior Marketing Analyst: Dina A. Maeder
`Fulfillment Manager: Stephanie DeNardi
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`r?»
`"i
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`"
`
`Copyright © 2000 and published by Medical Economics Company, lnc. at Montvaie, NJ 07645-1742. All rights reserved. Ndne of the content of this publication may
`be reproduced, stored in a retrieval system, resold, redistributed, or transmitted in any form or by any means (electronic, mechanical, photocopying, recording, or
`«) without the prior written permission of the publisher. PHYSICIANS‘ DESK REFERENCE", PDR', PDR For Ophthalmol
`
`‘ 1
`
`‘icaI Economics Company: President and ChiefExecutive Officer: Curtis B. Allen; Vice President, New Media: L. Suzanne BeDeil; Vice President, Corporate Human
`‘a M. Bilash; Vice President and Chief Information Officer: Steven M. Bressler; Chief Financial Officer: Christopher Caridi; Vice President and Controller: Barry
`t, New Business Planning: Linda G. Hope; Vice President, Business Integration: David A. Pitler: Vice President, Finance: Donna Santarpia; Senior Vice President,
`"aul Walsh; Senior Vice President, Operations: John R. Ware; Senior Vice President, Intemet Strategies: Raymond Zoeller
`
`

`

`PRODUCT INFORMATION
`
`'
`
`‘
`
`_.
`
`20—249 mog/mL
`
`25—30 meg/m1.
`
`>30 mcg/mL
`
`Decrease dose by 25% even if no
`adverse effects are present. Reoheck
`serum concentration afier 3 days to
`guide further dosage adjustment;
`Skip next dose and decrease
`subsequent doses at least 25% even
`if no adverse efi‘ects are present.
`Recheck serum concentration alter 3 V
`days to guide further dosage
`adjustment. If symptomatic,
`consider whether overdose
`treatment is indicated (see
`recommendations for chronic
`overdosage).
`Treat overdose as indicated (see
`recommendations'for chronic
`overdosage). If theophylline is‘
`subsequently resumed, decrease
`dose by at least 50% and recheck
`serum concentration after 3 days to
`guide further dosage adjustment.
`
`I Dose reduction and/or serum theophylline concentrafion
`measurement is indicated whenever adverse efi‘ects are pre-
`sent, physiologic abnormalities that can reduce theophylline
`clearance occur (e.g., sustained fever), or a drug that inter-
`acts with theophylline is added or discontinued (see WARN-
`INGS).
`
`.
`HOW SUPPLIED
`Uniphle (thqophylline, anhydrous) 400 mg Controlled—
`Release Tablets are supplied in white-opaque plastic bottles
`containing 100 tablets (N'DC 0034-7004-80) or 500 tablets
`(NDC 0084-7004-70).
`Each round, white, scored 400 mg tablet bears the symbol
`PF on one side and'is marked U400 on the other side.
`.
`Uniphyl® (theopliylline, anhydrous) 600 mg Controlled-
`Release Tablets are supplied'in white-opaque plastic bottles
`containing 100 tablets (N'DC 0034—7006-80).
`Each rectangular, concave, white 600 mg scored tablet bears
`the symbol PF on one side andis marked U600 on the other
`side.
`Store at controlled room temperature 15°—30°C (ESP—86°F).
`Dispense in tight light-resistant container.
`The Purdue Frederlck Company
`'
`Nomelk. CT 06850-3590
`Copyright ©1996,1998 The Purdue Frederick Company
`U.S.Patent Numbers '4,366,310
`June 15,1998 $1374
`Shown'inProduct Identification Guide, page 333
`
`EDUCATIONAL’MATERIAL
`Medication Induced Constipation continuing education pro-
`gram for pharmacists. Available at www.powerpak.com
`Website containing pain management information ’for
`health care professionals and patients Available at
`www.partnersagainstpain.com
`
`'
`
`EDUCA‘HONAL MATERIAL '
`
`LaxativeProtocol Sheets(00PS77) 1 page (pad of 25)
`.
`Available to. physicians, nurses and pharmacists
`
`
`Purdue Phaima LP.
`100 connecrlcur AVENUE
`uonvaLK, crooasoosso,, .
`
`.
`
`For Medical Inuuiries:
`,
`888-726.7535
`Adverse Drug Experiences.
`888-726-7535
`-
`,
`.
`Customer Service:
`-
`800-877-5666
`FAX 800-877-3210.
`
`‘
`
`,
`
`i
`
`-,
`
`-
`'
`
`MS ContinO Tablets—see listing under The Purdue FrederJ
`ick Company, page 2524
`MSm® Capsules—see listing under The Purse Frederick
`Company, page 2527 .
`
`MSmD Tablets—see listing under The Purdue Frederick
`Company, page 2527
`,
`
`items Liquid—see listing under The Purdue' Frederick
`Company, page 2527 ,
`.
`.
`
`
`
`
`@ E
`OXYCONTINQ
`lOXYcODONE HCI CONTROLLED-RELEASE) TABLETS
`10m920mg40m980mg
`
`:
`
`80 mg For use in opioid tolerant patients only.
`DESCRIPTION
`OXYCON’I‘IN® (oxycodone hydrochloride controlled--re-
`lease) tablets are an opioid analgesic suppliedin 10 mg, 20
`mg, 40 mg, and 80 mg tablet strengths for oral'administra’v
`tion. The tablet strengths describe the amount of oxycodone
`per tablet as the hydrochloride salt. The structural formula
`for oxycodone hydrochloride is as follows:
`
`
`
`MW 351.53
`cur-121m. - HCl
`The chemical formula1s 4, 5-epoxy--14-hydroxy—3-methoxys
`17~methylmorphinan-6—one hydrochloride:
`Oxycodoneis a white, odorless crystalline powder derived
`from the opium alkaloid, thebaine. Oxycodone hydrochlo-
`ride dissolves in water (1 g in 6 to 7 mL). It is_slightly sol-
`uble inalcohol (octanol water partition coefiicient 0.7). The
`tablets contain the following inactive ingredients: ammonia
`methacrylate copolymer,:hydroxypropyl methyloellulose,
`lactose, magnesium stearate. povidone, rediiron oxide (20
`mg strength tablet only), stearyl alcohol: talc, titanium di—
`oxide, triacetin, yellow iron oxide (40 mg strength tablet
`only), yellow iron oxide with-.FD&C blue No. 2 (80"mg
`strength tablet only); and other ingredients.
`OXVCONHNO 80 mg Tablets ARE FOR USE IN OPIOID TOL-
`ERANT PA11ENTS ONLY.
`_
`.
`.
`'
`CLINICAL PHARMACOLOGY
`'
`Central Nervous System ’
`‘
`-
`.
`oxycodoneis a pure agonist opioidwhose principal thera-
`peutic action'is analgesia. Other therapeu’fic efl'ects of oxy-
`codone include anxiolysis, euphoriaand feelings of relax-
`ation Like all pure opioid agonists, thereis no ceiling elfect
`to analgesia, such as is seen with partial agonists or non-
`opioid analgesics
`The precise mechanism of the analgesic action is unknown.
`However, specific CNS opioid receptors for endogenous com-
`pounds with opioid—like activity have been identified
`throughout the brain and spinal cord ‘and play a role'in the
`analgesic efi‘ects of this drug.‘
`Oxycodone produces respiratorydepression bydirect action
`on brain stem respiratory centers. The respiratory depres-
`sion involves both-a' reduction in the responsiveness of the
`brain‘stem respiratory centers to increases in carbon- diox-
`ide tension and to electrical. stimulation.
`,
`.
`Oxycodone depresses the cough‘reflex by direct efl‘ect on the
`cough center in the medulla. Antitussive effects may occur
`with doses 'lower than those usually required for analgesia.
`Oxycodone causes miosis, even in total darkness. Pinpoint
`pupils are a sign ofopioul‘overdose but are not pathognt‘r
`monic. Marked mydiiasis rather than miosis may be seed
`due to hypoxiain overdose situations
`’
`Gastrointestinal float and Other Smooth Muscle
`Oxycodone causes a reduction in motility associated with an
`increase in smooth muscle tone in the ’antrunr of the stom-
`ach and duodenum. Digestion offood in thesmall intestine
`is delayed and propulsive contractions are decreased; Pro-
`pulsive peristaltic waves in'tbe caldn are decreased, while
`tone may be increased to the point of spasm resulting in
`constipation: Other opioid4induced efi‘ects'may include a re
`ducfionin gastric, Biliary and pancreatic secretions, spasm
`ofsphincter of Oddi, and transient elevationsin serum am-
`ylase.
`Cardiovascular System
`Oxycodone may produce release of histamine with or with-
`out associated peripheral vasodilation Manifestations of
`histamine release and/or peripheral vasodilation may in-
`clude pruritus, flushing, red eyes, sweating, and/or ortho-
`static hypotension.
`Concentration—'Efi'icacy Relationships (Pharmacodynam-
`ics)
`Studiesin normal volunteers and patients reveal predict,
`able relationships between oxycodone dosage and plasma
`oxycodone concentrations, as well asbetween concentration
`and certain expected opioid efi'ects. In normal volunteers
`these include pupillar'y constriction, sedation and overall
`“drug eli‘ect” andin patients, analgesia and feelings of 're-
`laxation." In non--tolerant patients, analgesia'is not usually
`us/mL
`seen at a plasma oxycodone concentration of less than 5—10
`As with all opioids, the minimum efl'ective plasma concen-
`tration for analgesia will vary widely amongpatients, espe-
`cially among. patients who have: been previously treated
`with potent agonist opioids. As a result, patients need to be
`treated with individualized titration ofdosage to the desired
`effect. The minimum effective analgesic concentration of
`oxycodone for any individual patient may increase with re«
`peated dosing due to an increase in pain and/or the devel-
`opment of tolerance.
`Concedtration—Adoerse Experience Relationships
`OXYCONTIN tabletsare associated withtypical opioid-
`re1a't’ed adverse experiences similar to those seen withim-
`
`PURDUE PHARMA/2537
`
`mediate-release oxycodone and all opioids. There is a gen-
`eral relationship betweenincreasing oxycodone plasma con-
`centration andmcreasing frequency of dose-related opioid
`adverse experiences such as nausea, vomiting, CNS effects"
`and respiratory depression. In Opicid-tolerant patients, the
`situation is altered by the development of tolerance to
`opioid-related side effects, 'and the relationshipispoorly un-
`derstood.
`_
`As with all opioids, the dose must be individualized (see
`DOSAGE AND ADMINISTRATION), because the effective
`analgesic dose for some patients will be too high to be toler-
`ated by other patients.
`.
`.
`PHARMACOKINETICS AND METABOLISM
`The activity of 'OXYCONTIN® (oxycodone hydrochloride
`controlled-release) tabletsis primarily due to the parent
`drug oxycodone. OXYCONTIN tablets are designed to pro-
`vide controlled delivery of oxycodone over12 hours. Oxy-
`codone'is well absorbed from OXYCONTIN tablets with an
`oral bioavailability of from 60% to 87%.»The relative oral
`bioavailability of OXYCONTIN to immediate-release oral
`dosage forms is 100%. Upon repeated dosing in normal vol-
`unteers, steady-state levels-'were achieved within 24—36
`hours. Dose proportionality has been established for the 10
`mg, 20 mg;-40 mg, and 80 mg tablet strengths for both peak
`plasma levels.(C,,,u) and extent of‘absorption (AUC). Oxy-
`codone is extensively metabolized and eliminated primarily
`in the urine as both conjugated and unconiugated metabo-
`lites. The apparent elimination half-life ofoxycodone follow-
`ing the administration of OXYCONTINwas 4.5 hours com-
`Absorption
`'
`pared to 3.2 hours for immediate-release oxycodone.
`About 60% to 87% ofan oral dose of oxycodone reaches the
`central compartment in comparison to a parenteral dose,
`This high oral bioavailability is due to low‘pre-systemic
`and/or first-pass metabolism. In normal volunteers the tit of
`absorption-is 0.4 hours for immediate-release oral oxy-
`codone. In contrast, OXYCONTIN tablets exhibit a biphasic
`absorption pattern with two apparent absorption half-times
`of 0.6 and 6.9 hours, which describes the initial release of
`oxycodone from the tablet followed by a prolonged release.
`
` "olza’asare‘o
`
`I!)
`1‘
`Humrmoaw'
`+10“ +mma +4011: Ornmwml
`*nuuqlailhm-em-
`
`12
`
`.
`
`Does proportionality has been established forthe 10 mg, 20
`mg, 40 mg, and 80 mg tablet strengths for both peak plasma
`concentrations (Cm) and extentof absorpfion (AUG) (see
`Table 1 belovi). Given the short half-life of elimination of
`oxycodone;from OXYCONTIN, steady-state plasma concen-
`trations of oxycodone are achieved within 24—36 hours of
`initiation of dosingwith OXYCONTll‘l tablets. In a study
`comparing 10mg ofOXYCONTINevery 12 hours to 5 mg of
`immediate—release oxycodone every 6 hours, the two treat-
`merits werefound to be equivalent for AUC and Cw, and
`similar forC,“ (trough) concentrations. .There was less
`fluctuation'in plasma concentrations for the OXYCONTIN
`tablets than for the immediate-release formplafion.
`[See table 1 attop of next page]
`Food Efi‘écts
`'
`_‘
`In contrast toimmediate-release formulations, food has no
`significant efi'ect on the absorption of oxycodone from OXY-
`CONTIN. Oxycodone release from OXYCONTIN tablets'1s
`pH independent
`Distribution
`‘
`i
`"
`Following intravenous administration, the volume of'
`bution (Vss) for oxycodonewas 2.6leg.Oxycodonebinm
`to plasma protein at 37°C and_a pHof 7.4 was about 45%.
`once absorbed, oxycodone'is distfibuted to skeletal muscle,
`liver, intestinal tract, lungs, spleen and brain. Oxycodone
`Metabolism
`‘
`has been found'in breast milk (see PRECAUTIONS)
`Ox'ycodone hydrochloride is extensively metabolized to
`noroxycodone, oxymorph‘one, and their glucuronitles. The
`major circulating metabolite'is nomrwcodone with anAUG
`ratio of 0.6 relativeto that of oxycodone: Noroxycodone'is
`reported to be' a considerably weaker analgesic than oxy‘
`codone. Oxymorphone, although possessing analgesic activ-
`ity, is present in the plasma only in low concentrationst
`correlation betweenoxymorphone-concentrations and'opioid
`efi‘ects was much less than thatseen with oxycodoneplasma
`tabolitesis not known at present.
`concentrations. The analgesic activity profile of other me-
`The formation of oxymorphone, but not noroxycodone,is
`mediated by CYP2D6and as such its formationcan, in the-
`Excretion
`ory, be afi'ected by other drugs (seeDrug-Drug Interactions).
`Oxycodoneand its metabolites are excreted primarily via'
`the kidney. The amounts measuredin the urine have been
`
`Continued on next page
`Consult'zo oo~mflfiurpplememxand tuture‘ediflone for revleione
`
`

`

`PHYSICIANSl DESK REFERENCE®
`maslnuaous PHARMA
`
`Table 1
`.
`'
`'
`- ,
`Mean »[% coefficient variation]
`Regimen/
`,
`. AUG
`Cmnx
`.
`Tm,
`Trough
`Dosage Form
`(ngOhr/mLfi
`(ng/mL)
`'
`(his)?
`Cone.
`
`.
`.
`.
`.
`_.
`.
`.
`.
`.
`—
`..
`,
`(us/mi.)
`SingleDose
`..
`.
`.
`.
`'-
`10 mg OXYCONTIN
`100.7 [26:61.
`.
`.-:10.6[20.1l
`_
`2.714.411
`ms.
`
`
`20 mg oliIIICQN'II‘m"IIfl.I
`«
`.2073 [35.91
`r...
`I.21.4 [36.61
`3.2 {57.9}
`n.a.
`
`iomg oxvcoNTIN
`42341333)
`39.3 [34.01
`3.11774]
`-
`n.a.
`
`80 mg OXYICONTIN“.
`I
`..I10IS5.5 [32.3]
`' 95.5 [32.1]
`2.1 [52.3]
`n.a.
`Multiple Dose
`I
`l
`10 mg OXYCONTIN
`;
`'
`
`Tablets q12h
`. 103.6 [38.6]
`15.1 [31.01
`3.2 [69.5]
`7.2 [43.1]
`1.6 [49.71
`7.4 [50.9]
`15.5 {28.8}
`99.0 (36.2]
`5 mg immediate-
`
`release q6h
`.
`.
`Tfor singledose AUC=AUCNMS for multiple—dose AUC=AUCM
`*data obtained While volunteers received naltexone which can enhance absorption:
`
`
`
`
`
`BROKEN, CHEWED OR CRUSHED OXYCONTIN TABLETS
`COULD LEAD TO THE RAPID RELEASE AND ABSORPTION
`OF A POTENTIALLV TOXIC DOSE OF_OXYCODONE.
`.
`Respiratory Depression
`Respiratory depression is the chief hazard from all opioid
`agonist preparations. Respiratory depression occurs most
`frequentlyin elderly or debilitated patients, usually follow-
`inglarge initial doses in non--tolera'nt-phtients, or when
`opioids are given ii'rconjunction with other agents that de-
`press respiration.
`Oxycodone should be used with extreme caution"inpatients
`With significant chronic obstructive pulmonary disease or
`cor pulmonale; and'In patients havinga substantially de-
`creased respiratory reserve,hypoxia, hypercapnia, or preex-
`isting respiratory depression. In such patients, even usual
`therapeutic dosesI of oxycodo‘neImay decrease respiratory
`drive to the point of apnea,‘ In these patients alternative
`IlonLopioid analgesics should be considered, and opioids
`atthe lowest efi'ective dose.
`'
`should beemployed only under careful medical supervision
`Head Injury
`‘
`The respiratory depressant efl‘ects ofopioids include carbon
`dioxide retention and secondary elevation ofcerehrospinal
`fluid pressure, and may be markedly exaggeratedIn the
`
`presence of head injury, intracranial lesions, or other
`sources ofpreexisting increased intracranialpressure.
`codone produces efiects on pupillary response and co -
`sciousness which may ob’sIcurIe neurologiosigns offurtherin-
`creases in intracranial pressure in patients with head'Inju-
`nes.
`Hypotensive Effect
`OXYCONTINQ, like allopioid analgesics,may cause severe
`hypotensionin an individual whose ability to maintain
`blood pressure has been compromised bya depleted blood
`drugs such
`as phenothiazinesor other agents
`motor tone.0XYCONT1'N may produce "orthostatic' hypoten-
`aion in ambulatory patients. OXYCONTIN, likeall opioid
`analgesics, should be administered with, caution to patients
`in circulatory shock, since vasodilation producedby the
`drug may further reduce cardiacoutputand blood pressure.
`.
`PRECAUTIONS
`.r ,m
`_
`_
`J
`S ecial
`recautionsI
`ardin OXYCONTINO so In Tablets
`OXYOQNTINO so mg-Tablets are for use only in opioid tol-
`erant patients' requiring dIailyII oxyc'odllne equivalent dos-
`ages of 1so mg or more. Car‘s should be takenin the pre-
`scription of this tablet strength. Patients should be in-
`structed against use by individuals other than the patient
`for whom it was prescribed, as such inappropriate Hum-y
`
`have severe medicalconsequences.
`.
`
`General
`I‘
`”
`OXYCONTIN® (oxycodoné-hydrochloridecontrolled-re-
`lease) tablets are intendedfor use in pdfiellti‘vthorequire
`oral pain therapy With an opioid agonist of more than a few
`days duration. As with any opioid analgesic, it is critical to
`adjust the dosing regimen individually for each pa out (see
`DOSAGE AND ADMINISTRATION)
`:
`‘
`*
`Selection of patients for treatment with OXYCONTIN
`should be governed by the same principlesthat‘apply tothe
`use of similar controlled-release opioid analgesics (seIé IN:
`DICATIONS AND USAGE). Opioid analgesicsgiven'on a
`fixed-dosage schedule have a narrow therapeuticdnd‘exIn
`certain patient populations, especially when combined with
`other drugs, and should be reserved for cases Where the
`benefits ofopioid analgesia outweigh the known risks ofres-
`piratory depression, altered mental state, and postural hy-
`potension. Physicians should individualize tifeatmentin ev-
`ery case, using non-opioid analgesics, pro opioids and/or
`combination products, and chronic opioid therapy with
`drugs such as OXYCONTINIn a progressive plan of pain
`management such as outlined bythe World Health Organi-
`zation, the Agency for Health Care Policy‘and Research, and
`the American Pain Society.
`Use of OXYCONTIN'18 associated With*increasedpotential
`risks and should be used only with cautionIn the following
`conditions: acute alcoholism; adrenocortical insufficiency.
`(e;g.,‘Addison's disease); CNS depression ‘or coma; delirium
`tremens; debilitated patients; kyphoscoliosis associated
`with respiratory depression; myxedema or hypothyroidism;
`
`"
`
`,
`
`OxyContin—Cont.
`reportedasfollows: free oirycodone up to 19%; conjugated
`oxycodo'ne up to 50%; free oxymorphone 0%; conjugated oxy-
`momhone S‘14%; both frail andconjugated noroxycodone
`
`have been foundIn the urine but not quantified The total .
`plasma clearance was 0.8 L/min for adults.
`Special Populations
`
`Elderly
`The plasma concentrations ofoxycodone areonly nominally
`affected by age, being 15% greaterIn elderly ascomparedto
`young subjects. There were no _d_ifi"erences'In adverse event
`reporting between young and elderly subjects
`.
`._ ,
`.
`Gender
`Female subjects have, on average, Iplasma orineodone(con-
`centrationsup to 25% higher than males on a body .Weight
`adjusted basis. The reason for this difi'erenceIs unknown.
`Renal Impairment
`'
`Preliminary data from a studyinvolvri'lIIg patients With mild
`to severe renal dysfunction (creatinineclearance. <60 mL/
`min) show peak plasma oxycodone and noroxycodone..con-
`centrations50% and 20%higher, respectively andAUC val-
`ues for oxycodone, noroxycodone and oxymorphone- 60%,
`50% and 40% higher thail‘rnormal subjects,.respectively
`In patients with cancer pain, the total daily OXYCONTIN
`This is accompanied by an incl-casein sedation but not by
`doses tested rangedfrom 20 mg to 640 mg per day. Theav-
`difi‘erences in respiratory rate, pupillaryconstriction; or
`several other measures ofdrug efiect. There was an increase
`Studiesin NoneCaricer Pain
`'
`erage total daily dosewas approximately 105 mg per day.
`CAUTIONS)
`~
`« ~-
`in tllfi of elimination for oxycodone ofonly: 1 hour (see PRE-
`A double-'blind, placebo-controlled, fixed-dose, parallel
`group study was conductedin 133 patients with moderate to
`Hepatic Impairment
`!
`severe osteoartllritis’spain, who were judged as having inad-
`Preliminary data from a study involving patientsWith mild
`equate! pain: control -with‘ prn opioids and maximal non-
`to moderatehepatic dysfunctibn show peak plasmaoxy-
`steroidal antisinfiammatoryithe‘rapy- In this study, 20 mg
`codone and noroxycodéne concentrations 50% and 20%
`OXYCONTIN quh‘tsignificantly decreased pain'and im-
`higher, respectively, than normal subjects. AUC valuesare
`proved quality: of life, moodand sleep, relative to placebo.
`95% and 65% highor, respectively. Oxymorph’one peak
`Bothldose-concenlnation and concentration-effect relation-
`plasma concentrations and AUC values ‘are lower by 30%
`ships were noted With'a‘ minimum efl‘ective plasma Olive-
`and 40%: These difierences are accompanied byincreases in
`odil‘u'e concentration of approximately 5-110 ng/mL.
`.
`some, but not other, drug‘efi'ects. The t% elimination for
`In a double-blind, active-controlled; crossover study involv-
`oxycodone increased by 2.3 hours (see PRECAUTIONS).-' ‘
`Rectal Administration
`ing 57 patients with low-hack pain inadequately controlled
`with prn opioids and non-opioid therapy, OXYCONTIN ad-
`Rectal administration of OXYCONTIN tabletslsnot recom‘
`ministered q12h provided analgesia equivalent fodmmedt
`mended. Preliminary data from a studyinvolving 21 normal
`ate-release oxycodone administered qid.Patients could be
`volunteers, show OXYCONTIN tablets administered per
`titrated to.a.nacceptable analgesicclient with eitherOIXY-
`rectum resulted'In an AUG 39% greater and a Cm 9%
`CONTIN Ior immedmmrdease forms of oxycodone
`TIONS).
`higher than tablets administered by mouth (see PRECAU-
`..
`SingleDose Comparison with Standard Therapy
`A single-dose, double-blind, placebo—controlled, post-opera-
`Drug--Drug Interactions (see PRECAUTIONS)
`tive study of182 patients was conducted utilizinggraded
`OxycodoneIs metabolized'In part .via’ CYP2D6 to oxymor-
`doses of OXYCONTIN.(10, 20 and 30 mg) Twenty and 30
`phone which represents less than 15% of the total adminis-
`mg of OXYCONTIN gave equivalent peak analgesic effect
`tered dose. This route of elimination can be blocked by a
`compared to two onycodOne 5 mg /acetaminophen 325 mg
`variety ofdrugs (e.g., certain cardiovascular drugs and anti-
`tablets and to 15 mg immediate-release oxycodone, While
`depressants). Patients receiving such drugs concomitantly
`the 10 mg dose oi;,OXYCQNTIN was intermediate between
`with OXYCONTIN do not appear tapresent dlfi'erent ther-
`both theMediate-release and combination pi-oductsand
`apeutic profiles than other patients
`placebo. The onsetofanalgesic action with OXYCONTIN oc-
`CLINICALTRIALS
`’
`currIed within 1 hour'In most patients following oral admin-
`istration.
`OXYCONTINQ (oxycodone hydrochloride controlled-re-
`OXYCONTIN'Is not.reponlmehded pre-operatively (preemp-
`lease) tablets were evaluated in studies involving 713 pa-
`tiveanalgesia) or for the management of pain in the'unme-
`tients with either cancer or non«caIncer pain. All patientsre
`diatepostoperative period (the first 12 to 24 hours follow-
`ceiving OXYCONTIN were dosed- 91211. Eflicaoy comparable
`ing surgery) because the safety or appropriateness offixed-
`to otherforms’'of bin onycodohéwas demonstratedIn “lini-
`i
`1..“
`cal studies using pharmacolnnfetlc, pharmacodynamic ‘and
`dose, long-acting opioids in thissetting has not been
`established...
`efficacy outcomes The outcome 'of these trials indicated: ('1)
`Other Clinical Thais
`.
`,
`.
`a positive relationshipbetween‘dose and plasma oxycodone
`In open--label trials involvingapproximate1y 200 patients
`concentration, (2))apositille relationship betWeen plasma
`oxycodone concentration and dualgesla, and (3)an observed
`with cancer-related and non-cancer pain, dosed according to
`the packageipsert recommendations, appropriate analgesic
`peak to trough variationinplasma concentration withOXY-
`efi'ectivenesawfieveas notedwithout regard to age, gender, race,
`CONTIN lying Within the observedrange established with
`or disease state. There were no unusual drug interactions
`q'id ‘dosing ofimmediate-release oxycodorle'In clinicalpopu4
`observedin patients receiving awide range of medications
`lations at the sametotal‘ daily dose.
`‘
`common in these populations.
`;
`v.
`In clinical ti'ial's, OXYCONTIN tabletawere subs‘fituted for
`Foropioid-naive patients, the average total, daily dose oi
`a Wide variety of analgesics, I’iIncludiIng‘ acetaminophen
`OXYCONTIN was approximately 40 mg per day. There was
`(APAP), aspirin (ASA), other non-steroidal anti-momma:
`
`no evidence of oxycodoneand metaboliteammulation dur-
`0on drugs(NSAIDIs)opioid combination products and sin-
`ing 8 Inlonths of therapy. For cancer pain patienm the aver-
`gle-entity opioids; ‘pII'irInarily morphine. Incancer patients
`age total daily dose was 105 mg (range 20 to 720 mg) per
`day. There was. a significant decreaseInacute opioid-related
`receiving adeirua‘te opioid therapy at baseline, pain inten-
`sity scores and acceptability of therapy remained un-
`sideeifects, except for constipation, during the first several
`changed by transfer to OXYCONTIN. For non-cancer pain
`weeksoftherapy. Developmentof significant. toleranceto
`analgesia.was uncommon.
`.
`.
`patients who had moderateto severepain‘ at baseline on prIi
`opioid therapy, pain cohml slid acceptability oftherapyim—
`A cohort of patients have been maria with oxrcomj‘ln
`L
`proved withthe introductionof fix‘ed—interval therapy With
`OXYCONTIN.
`80 mgtablets. There were no difi‘ereilcesgin the ehicacy or
`safety profiles than seenwith the other tablet strengths.
`INDICATIONS AND USAGE
`‘
`.
`.I. .:
`Use'InConcerI Pain ..
`
`OXYCONTIN was studied'in three double-blind, controlled
`clinical trials involving 341 cancer patients and several
`OXYCONTIN® tablets are a condoned-release oral formu-
`open-labeltrials with therapy durations of over 10 months.
`lation ofoxycodone hydrochlorideIndicated for the manage
`Two, double—blind,controlled clinical studies indicated that
`merit of moderate to seVere pain whereuse of an opioidan-
`OXYCONTIN dosedmlzhproduced analgesic efiicacy equiv-
`alges'ic1's appropriate mm morethana few days. (See:CLIN—I
` #1-.I
`alent to mimediate-release oxycodone dosedqid at the same
`ICAL PHARMACOLOGY; CLINICALTRIALS)
`CONTRAINDICATIONS a»
`total daily dose. Peak and trough plasma concentrations at-
`tained.;were similar to<those. attained with immediate-re-
`OXYCONTIN®Is contraindicatedin patients With known
`lease oxycodone-at,equivalent total daily doses; With titra-
`hypersensitivity to oxycodo'ne; or in“ any situation Where
`tion to analgesic efi'ect and proper use of rescue medication,
`opioids are contraindicated. This includes patients with sig-
`nificant respiratory depression (iI'I‘ onmonitored settings‘or
`nearlyev.ery patient achieved adequate pain controlwith
`OXYCONTIN.
`, , a. W
`.
`the absence ofiresuscltative equipment);andipatients with
`In the thirdstudy, a double-blind, aotiveI-controlled, cross-
`acute or‘severe bronchial asthmaor hypercarbia. OXYCON-
`over trial, OXYCONTIN dosed q-12hwasshown to be equiv-
`alent insflicacy and safety.“ immediate~release okycodone
`x
`TIN'Is contraindicatedinany patient who hasor is sus-
`dosed qid at the same total daily dose. Patients were~ableto
`pected ofhavingparalytic ileus.
`-
`:-
`v
`.
`WARNINGS
`"
`be titrated‘to Ean acceptable analgesic sheet with‘ either
`OXYCONTIN or immediate-release oxycodo'ne.with both
`OXYCONTINQ (oxycodona hydrochloride controlled-re-
`lease) TABLETS ABEIJTO.BE. SWALLOWED WHOLE, AND
`treatments providing stable pain control within 2 daysIn
`most patients» ..
`g,
`, r1,
`..
`ARE NOT Toss BROKEN; CHEWEDOR CRUSHED. TAKING
`Information -wlll. be supersededbvsupplements and subaaquenmditions
`
`

`

`Mir—w
`
`
`
`PRODUCT"ilNFORMATlGN‘ 3.. :
`
`prostatic hypertrophy or uretln-sl stricture; severe impair-
`chosis.1;
`ment ofhephtichpulmonary orrenal function; and toxicpsy-
`The adnirmstratmn‘of oxycodone; like all opioid analgesics;
`may obscure thediagnosis or clinical course in patientsWith
`acute. abdominal conditions:Oxycodone mayaggravate‘ cone
`vulsion's in patients with convulsive disorders, and all‘opio-
`
`ids may induce or aggravate seizures in some clinical
`t=
`tings1-vv"’1‘
`unsa‘
`‘
`Interactions with other CNS Depressants
`-
`‘
`OXYCON‘I‘IN, like 1111‘ opioid analgesics, should be used
`with caution arid started111 a reduced dosage (1/9 to 1/2 ofthe
`usual dosage)1n patients‘Who are concurrently receiving
`other central nervous system depressants including seda-
`tives or hypnotics, general anesthetics,-Iphonothiazines,
`other tranquilizers and alcoholInteractive efi‘ectsresulting
`in respiratory depression, hypot'ension, profound sedation
`or coma may result if these drugsare takenm combination
`with the usual doses ofOXYCONTIIN.
`'
`51:69
`Interactions with Mixed Agbnist/Arrtagorrist OpioidAnalge-
`Agomst/antagomst analgesics (i.e., pentazocine, nalbu-
`phine, butb‘rphanol and buprenorphme)should be adminis-
`tered With caufion to apatient whohas received or '
`receiv-
`ing a course of therapy with apure opioidagonist analgesic
`such as oxycodone. In this situation, mixed agonisflautago-
`nist analgesics may reduce the analgesic efl'ect ofoxycodone
`tients."
`,
`and/or may precipitate withdrawal symptoms1nIthese pa-
`Ambulatory Surgery ’I
`'
`‘
`QXYCONTIIN1s not rechmniended pro-operatively (preemp-
`ti’ve analgesia) orfor the management of pain in the'unme-
`diate post-operativeperiod(the first 12 to 24hours follow-
`ing surgery)ibr patientsnot previously taking the drug, be-
`cause its safetyI'In this settinghas notbeen established;
`Patients who are already receiving OXYCONTIN tablets as
`part of ongoing analgesic therapy may be safely continued
`on the drug if appropriate dosage adjustments are made
`considering the procedure, other drugsgiven slid the Item-
`porary changes'in physiolo caused by the surgicalinter-
`vention (see PRECAUTION:
`rug-DrugInteractions, and
`DOSAGEANDADMDHSTRATION)
`.
`.
`Post——Operntipe Use
`I
`Morphine and other opioids,haveI beau shown to decrease
`bowel motility. Ileus'1s a common postoperative complica-
`tion, especially alter intrarabdominal. surgery with opioid
`analgesia Caution should be taken to monitor for decreased
`bowel motility1n post-operative patients receiving opioids.
`Standard supportive therapyshould be implemented.
`Use'in Pancreatic [Biliary 11m: Disease
`Oxycodone may cause spasm of the sphincter of Oddi and
`should be used withcautioni'In patients with biliary tract
`disease, includingacute pancreatitis. Opioids like oxy-
`codone may cause increases in the serum amylase level.
`Ible‘ranc‘e andPhysical Dependence
`’lblerance'15 theneed firr'mcreasing dosesofop1o1ds to main-
`tain' a defined effect such as analgesia (in the absence ofd1s-
`ease progression or other externalfactors) Physical depen-
`dence 1's ~‘the occurrence of withdrawal symptoms after
`abrupt discontinuationof a drug or upon administration of
`an antagonist. Physical dependence and tolerance are not
`‘ unusual during chronic opioid therapy.
`'
`Significant tolerance should not occur in most of 'the pa-
`tients treatedwith the lowestdodes of Oxycodone, It should
`beexpected, however, that a fi'action of cancer patients Will
`
`developsome degree of toleranceand require progressively
`
`higher dosages of OXYCONTINto maintain
`ntrol
`dunng chronictreatment.Regardless ofwheth